Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03592069 |
| Other study ID # |
AlexandraH |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
February 21, 2018 |
| Est. completion date |
January 31, 2021 |
Study information
| Verified date |
August 2021 |
| Source |
Alexandra Hospital, Athens, Greece |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
10 day concomitant versus 14 day hybrid regimen as first line H. pylori eradication treatment
in a high clarithromycin resistance area. A multicenter, randomized, equivalence trial.
Description:
RESEARCH PROTOCOL:
TITLE "10 day concomitant versus 14 day hybrid regimen as first line H. pylori eradication
treatment in a high clarithromycin resistance area. A multicenter, randomized, equivalence
trial."
INTRODUCTION
Helicobacter pylori (H. pylori) is a global human pathogen implicated in the pathogenesis of
prevalent and serious diseases mainly peptic ulcer disease and gastric malignancy.1 Recent
guidelines propose H. pylori eradication every time that it is found with the usual detection
methods.2 Successful eradication largely depends on the choice of antibiotics in which the
microbe is mostly sensitive.3 Usual first line therapies contained a proton pump inhibitor
(PPI) and two antibiotics, clarithromycin with amoxicillin or metronidazole when amoxicillin
wasn't indicated.4 Eradication rates have been initially acceptable reaching over 80% in per
protocol analyses.5,6 However in late years H. pylori has developed an increasingly high
resistance profile which has reached over 20% in most European countries, including ours. As
a consequence, eradication rates with triple regimens declined to percentages less than 80%
in per protocol analyses.7-9 Currently acceptable schemes include the already known bismouth
containing quadruple regimen and the non bismouth quadruples namely concomitant, sequential
and hybrid.10,11 In our country the 10 days concomitant regimen presents stable and high
eradication rates which are significantly better than the standard triple and sequential
regimens of the same duration.12-14 In two recent studies concomitant had a significant
advantage over sequential on metronidazole resistant strains as well as on dual resistant to
both clarithromycin and metronidazole strains.14,15 The hybrid regimen is the less studied
first line regimen in Europe.16 In a recent study, on a Greek population, a 14 days hybrid
regimen achieved encouraging results and the only predictive factor for failure has been dual
resistance.17 To date there hasn't been any comparative study between 10 days concomitant and
14 days hybrid regimens.16
PURPOSE OF STUDY The investigators designed an equivalence trial between the 10 days
concomitant and 14 days hybrid regimens in a Greek population.The investigators primary
outcome is to compare total eradication rates between these two regimens in intention to
treat and per protocol analyses. Secondary outcomes are to compare eradication rates in
respect to genotypic and phenotypic resistance profiles, the effect of antibiotic resistance
on therapy, patient's compliance, adverse events and economic evaluation of the two regimens.
PATIENTS - METHODS
Patient selection Patients of 18 years or older with dyspepsia / or iron deficiency anaemia,
referring for upper GI endoscopy and found to be infected with H. pylori (positive rapid
urease test), naïve to H. pylori eradication treatment, will be invited to participate in the
study. Exclusion criteria are: age below 18 years, presence of severe co-morbidities (i.e.
liver cirrhosis, renal failure, haematological, neurological, psychiatric, cardiovascular or
pulmonary disease), previous gastric surgery, gastric malignancies, Zollinger-Elisson
syndrome, known allergy or other contraindications to the study medications, previous H.
pylori treatment, use of antibiotics , bismuth salts , NSAIDS or aspirin in the preceding
month, use of PPI in the preceding two weeks and not willing to participate in the study.
Pregnant or lactating women will also be excluded.
Study Design The study will be prospective. Upper GI endoscopy including two antral biopsies
for rapid urease test (CLO-test) will be performed at each patient. In patients tested
positive two additional specimens (from the antrum and corpus) will be sent to a reference
laboratory for culture and antibiotic susceptibility tests. In cases with indication for
histology or equivocal CLO-test results, at least two specimens will be taken from the antrum
and corpus respectively, to confirm H. pylori gastritis using haematoxylin-eosin and modified
Giemsa staining. In equivocal cases an immunohistochemical method can be used. Patients
tested positive by urease test and/or histology will be allocated to either treatment group.
Every patient will sign an informed consent in order to participate in the study.
Additionally, a careful medical history will be obtained and complete clinical examination
performed (including appropriate blood or other tests if indicated) prior to inclusion into
the study.
Participants will be randomly assigned, in a 1:1 basis, to one of two treatment groups namely
concomitant and hybrid. Randomization will be organized centrally by an independent assistant
investigator using a computer-generated randomization method, using a block size of four.
This will produce a separate number for each patient sealed in an opaque envelope and kept in
his office throughout the study. After obtaining informed consent, the investigators would
call the research assistant to open the envelope for the allocated regimen. All data will be
inserted in a computer database and elaborated by the participating investigators. The trial
is not blinded for patients and recruiting physicians, regarding treatment regimen, as in
most randomized controlled H. pylori eradication trials.
Interventions
After the confirmation of H. pylori infection, eligible patients randomly assigned to either
concomitant or hybrid treatment group will receive:
- Concomitant for 10 days, including 40 mg of esomeprazole bid, amoxicillin 1g bid,
clarithromycin 500mg bid and metronidazole 500mg bid.
- Or Hybrid for 14 days, including 40 mg of esomeprazole bid and amoxicillin 1g bid, for
the first 7 days followed by esomeprazole 40mg bid, amoxicillin 1g bid, clarithromycin
500mg bid and metronidazole 500mg bid, for another 7 days.
Esomeprazole will be given before and antibiotics after meals, in both regimens. In the
post-treatment period, symptomatic patients will be allowed to use antacids on demand.
Antibiotics or other medications interfering with the treatment results will be prohibited
during the study period. Efficacy of treatment will be evaluated 4-6 weeks after completion
of antibiotic therapy by 13C-urea breath test (13C-UBT) performed according to the standard
European protocol. In patients requiring a follow-up endoscopy due to peptic ulcer disease,
persisting or recurring symptoms, the diagnostic test of choice will be histological
examination of four samples taken, in pairs, from the antrum and from the corpus and stained
by modified Giemsa.
Tolerability and adherence Side effects of treatment will be assessed on a structured
clinical interview with a specific questionnaire completed immediately after the end of
eradication therapy and at the final re-evaluation. During the interview, patients will be
asked to grade the severity of each adverse event experienced as "mild" (transient and well
tolerated), "moderate" (causing discomfort and partially interfering with common everyday
activities), or "severe" (causing considerable interference with patients' daily
activities).18 Incapacitating or life-threatening complications will be classified as serious
and will be reported to regulatory agency (National Organization of Medicines). Adherence to
treatment will be assessed by providing all patients with a pre-structured printed table with
all dosages illustrated, asking to tick each time a pill was consumed and bring it back along
with any tablet not consumed, for pill counting. In case of discrepancies found between the
structured printed table and residual medication, the latter will be taken into account to
evaluate patient's adherence. Poor adherence is defined as <90% of the total medication
taken.
Culture and antibiotic susceptibility tests Isolation of clinical H. pylori strains H. pylori
clinical strains will be isolated from gastric biopsies. All biopsies will be placed in
thioglycollate medium (Oxoid, Basingstoke, UK) and will be sent to the Laboratory of Medical
Microbiology (Hellenic Pasteur Institute) for H. pylori isolation within 2-4 hours after
endoscopy. Following addition of sterile glass beads, biopsy samples will be vigorously
vortexed and 100μl of homogenate will be cultured for up to 7 days, at 37°C under
microaerophilic conditions (CampyPak-Plus, Becton-Dickinson, Cockeysville, MD), on Columbia
agar plates containing antibiotics (vancomycin 10μg/mL, trimethoprim 10μg/mL, polymyxin B 104
IU/L, amphotericin B 2μg/mL, nalidixic acid 10μg/mL, bacitracin 30μg/mL and fluorocytosine
5μg/mL), supplemented with 8%v/v horse blood and 1% v/v Vitox (Oxoid, Basingstoke, UK).
Culture sweeps, as well as individual colonies will be collected and frozen at -80°C, until
used.
Antibiotic susceptibility testing Antibiotic susceptibility testing of H. pylori will be
performed utilizing E-test strips (BioMerieux, Marcy l'Étoile, France), according to the
manufacturer's instructions, on Mueller Hinton agar medium (Beckton Dickinson) supplemented
with 10% horse blood. Briefly, agar plates will be freshly prepared and used within 7 days
following their preparation. Bacterial inoculum will be prepared from a 1 or 2 day old
culture and bacterial suspension will be adjusted to McFarland 3 turbidity (approx. 108
colony forming units-CFU/mL). E-test strips will be applied with sterile forceps to the dried
agar surface, following application of the bacterial inoculum and plates will be incubated at
37°C under microaerophilic conditions. Results will be read at 72 hours. MIC clinical
breakpoints used to define resistance according to EUCAST will be: clarithromycin (>0.5
mg/L), levofloxacin (>1 mg/L), tetracycline (>1 mg/L), metronidazole (>8 mg/L) and
amoxicillin (>0.12 mg/L). To detect genotypic resistance to clarithromycin and levofloxacin a
real time PCR will be implemented in cultured H. pylori strains.
Sample size calculation The study is designed to prove or reject equivalence between the two
eradication regimens under study namely 10 days concomitant and 14 days hybrid (equivalence
trial). Based on the results of previous studies eradication rates over 85% in intention to
treat and over 90% in per protocol analyses have been found for both regimens.17 According to
international statistical rules (FDA) two regimens are considered equivalent when the
confidence intervals of the difference between their eradication rates do not exceed 15%.
Using the Monte Carlo (500 X 500 runs) simulation system and taken into account that in the
existing Greek studies14-16 eradication rates for hybrid regimen are between 86 and 90% in
intention to treat analysis we calculated a sample size of 150 patients in each treatment arm
(with a 10% drop out rate) in order to get an 80% power in the study.
Statistical analysis Comparisons of proportions will be done using the chi-square test.
Continuous non-parametric data will be compared using the t test. Stepwise multivariate
logistic regression analysis will be performed to evaluate factors influencing H. pylori
eradication in patients who had a final treatment outcome with either concomitant or hybrid
therapy.
